TiPS - December 1993 [Vol. 14] 435

Potassium channel nomenclature: a personal view Potassium channels are ion chan- nels that are both ubiquitous and highly diverse. The diversity of voltage-gated K-channels is manifested biologically in distinct voltage-dependencies and kinetics of activation and inactivation, in distinct sensitivities for extra- cellular and intracellular ligands (e.g. K +, Ca 2+, Mg 2+, ATP, cAMP, G proteins) in distinct single chan- nel behaviours such as mean open durations and conductance, and in distinct ion selectivities. Vari- ations in any one of these proper- ties appears to lead to a bewilder- ing number of distinct K-channels, the properties of which have been described for both excitable and non-excitable cells.

Remarkable progress has been made recently in the molecular biology of K-channels. This prog- ress has shed considerable light on the structural diversity of K- channels. Much has been learned about the structure of the proteins that form K-channels in in vitro expression systems, but determi- nation of the physiological roles of the cloned K-channel forming proteins is still a largely unsolved problem. Thus, it has to be realized that the presently existing no- menclature on cloned K-channel- forming proteins 1 is not, and cannot be, a nomenclature for K- channels; rather it is a unifying list of clone names, which may help to straighten out the Baby- lonian confusion on ion-channel cDNA clones, presently in use in many different laboratories. In this context, it is quite amusing to see that we have adopted one no- menclature for cloned human K- channel genes and another one for cloned K-channels encoded in non-human genomes. A nomencla- ture for endogenous K-channels has the burden of coping not only with the general diversity of K- channels, but also with the colt- fusion between K-currents and K- channels. Towards this end, it may be helpful to look over the fence to the nomenclature in other systems. A well worked out nomenclature that comes to mind is the one of enzymes. Enzymes are classified into main groups according to the general type of reaction that they catalyse. The

main groups are divided into sub- groups on the basis of substrate specificity. These are. further divided into subgroups, e.g. based on ions and cofactors required for activity. Finally, a fourth number is added as a serial number. For example, EC 3.4.17.1 stands for: EC, enzyme commission; 3, hydrolases as main group; 4, peptidases as subgroup; 17, metal- carboxypeptidase as a further sub- group; 1, serial number.

In my opinion, it would be very useful if the ion channel field could adopt a similar system. Although not everybody may agree with this, I can only empha- size that K-channels, like any other ion channels, are enzymes. After all, ion channels are integral membrane proteins that catalyse the flow of ions across the mem- brane. Therefore, I think that a discussion about K-channel no- menclature on one side and K-cur- rent nomenclature on the other, is superficial and detracts from the real issue. Such a discussion may be compared to a situation where one would argue about one nomenclature for enzymes and a separate one for reactions catalysed by enzymes. Thus, a future nomenclature should not attempt to refine or extend the present trivial ones. Here one should keep historical names in their own right, and not attempt to 'improve' them.

If one takes enzyme nomencla- ture as a guideline, then one could

start with ion channels in general. Main groups might specify which type of current the channel carries [e.g. cation (Na, Ca, K, H), anion (C1) or ionic (charged molecule) currents]. The first subgroup division might specify the chemical or physical agent that opens the channel (e.g. transmitter, ion, G protein, cyclic nucleotide or change in membrane potential). The second subgroup may refer to the Eisen- man ion selectivity series followed by a serial number.

A less than ideal nomenclature may be one that attempts to sub- divide ion channels according to their mode of inactivation (e.g. delayed rectifier or A-type) or according to channel conductance properties (e.g. small K or large K). Using this nomenclature, enzymes would have been classified as allosteric or non-allosteric pro- teins, or as fast or slow catalysts. Finally, biochemists still often use trivial names for their enzymes, largely for historical and senti- mental reasons. Thus, it is to be expected that any systematic nomenclature on ion channels would not entirely substitute or eliminate trivial names that are currently in use. However, a systematic K-channel nomencla- ture is clearly important for refer- ence, and should be established.

OLAF PONGS

Zentrum fiir Molekulare Neurobiologie, Institut fiir Neurale Signalverarbeitung, Martinistra/~e 52, Haus 42, D-20246 Hamburg, Germany.

Reference 1 G u t m a n , G. A. and C h a n d y , K. G. (1993~i

Sere. Neurosci. 5, 101-106

Channel nomenclature: IUPHAR recommendations The International Union of Pharmacology (IUPHAR) created a nomenclature committee to standardize terms, initially for receptors, but also for cell mem- brane channels. The core com- mittee consists of molecular biologists, chemists and industrial and academic pharmacologists and has established links with the International Union of Bio- chemistry and Molecular Biology (IUBMB) and the associated en-

zyme nomenclature committees. There are currently 17 subcom- mittees preparing recommendations on a range of receptor and ion channel systems and a technical subcommittee is preparing a gloss- ary of pharmacological terms and definitions. The calcium channel subcommittee has already issued its recommendations for no- menclature 1.

The formation of subcom- mittees is based on two criteria:

(~) 1993, Elsevier Science Publishers Ltd (UK) 0165-6147/93/$06.00

430 TiPS - December 1993 [Vol. 14]

need and feasibility of producing suitable recommendations. There is a limit to the number of sub- committees that can be run effect- ively. We initially quailed before the task of classifying potassium channels on the grounds that the difficulties were enormous, and we had not yet established suf- ficient guidelines. Our relative success in other areas does now allow us to form a subcommittee and the fact that Drs Edwards, Weston, Chandy, Gutman and Pongs feel sufficiently motivated to write about the matter results in their being asked to be founding members, together with the further addition of chemists, molecular biologists, electrophysiologists and pharmacologists.

An IUPHAR committee by definition represents the con- sensus view, but in other areas we have previously managed to

marry function with genetics. It is to be hoped that such a marriage will lead to a workable scheme in the case of potassium channels. Because such consensus takes some time to establish, IUPHAR will not be able to contribute to the current debate but refers readers to previous committee nomenclature directives 2,3.

Clear guidelines have been laid down as to how to classify chan- nels, using molecular b~ology, electrophysiological, biochemical and pharmacological criteria 1. These criteria are also applicable to potassium channels. Classifi- cations should not be based on just one experimental discipline. For example, Ii< obviously refers to potassium current, but in electro- physiology, this refers to the charge carrier and this well accepted convention should be adhered to. The pharmacology of

Ica often differs markedly from IBa, even if the channel is the same. This is the reason why we did not promote Edward and Westons' idea of ICa(L); it may also be danger- ous for Ii<, although K + is the most usual charge carrier. In addition, using S (for small) as a conductance descriptor may also be inadvisable when the main conductance unit is S (Siemen).

MICHAEL SPEDDING AND PAUL M. VANHOUTTE

Secretary and President, |UPHAR. no- menclature committee IdRS, 11 rue des Moulineaux, 92150 Suresnes, France.

References 1 Spedding, M. and Paoletti, R. (1992)

Pharmacol. Rev. 44, 363-376 2 Vanhoutte, P. M. (1992) Pharmacol. Rev.

44, 349 3 Kenakin, T. P., Bond, R. A. and Bonnet,

T. I. (1992) Pharmacol. Rev. 44, 351-362

Anti-inflammatory actions of steroids: molecular mechanisms Peter J. Barnes and lan Adcock

Glucocorticosteroids are highly effective in controlling inflammation and the molecular mechanisms involved are now becoming clear. Activation of glucocorticoid receptors results in increased or decreased transcription of a number of genes involved in the inflammatory process. Of particular importance is the repression of cytokine gene transcription and the direct interaction between the glucocorticoid receptor and other transcription factors activated in chronic inflammation. In this review, Peter Barnes and Ian Adcock discuss recent studies that have increased our understanding of these mechanisms and that may lead to improved anti-inflammatory therapies in the future.

Glucocorticosteroids are the most potent and effective agents in con- trolling chronic inflammatory diseases. Inhaled steroids have now become first-line therapy for chronic asthma, the most preva- lent inflammatory disease in in- dustrialized countries. There have

P. J. Barnes is Professor and I. Adcock is Lecturer in the Department of Thoracic Medi- cine, National Heart and Lung Institute, Dovehouse St, London, UK SW3 6LY.

been important advances in our understanding of the molecular mechanisms involved in the anti- inflammatory actions of steroids, largely through the application of molecular biology techniques. These new approaches have also given new insights into the basic mechanisms of inflammation and this may provide a basis for the development of more selective anti-inflammatory drugs in the future.

(~ 1993, Elsevier Science Publishers Ltd (UK) 0165 - 6147/93/$06.00

Glucocorticoid receptor Receptor structure

Glucocorticoids exert their effects by binding to a cytoplas- mic glucocorticoid receptor within target cells. The glucocorticoid re- ceptor is a member of a supergene family which includes cytosolic receptors for other steroid hor- mones, such as progesterone and oestrogen, for thyroid hormone and for retinoic acid and vitamin D (Ref. 1). Glucocorticoid receptors are expressed in almost every type of cell although the density of glucocorticoid receptors may differ from cell to cell. The inactive gluco- corticoid receptor is bound to a large protein complex (~ 300 kDa) that includes two subunits of the heat shock protein Hsp90, which binds at the C-terminal end of the receptor. There is also evidence that other proteins may be associ- ated with this complex, including a 59 kDa immunophilin protein and various other inhibitory pro- teins. Hsp90 may facilitate the proper folding of glucocorticoid receptors into a conformation that is optimal for binding and acts as a molecular chaperone to prevent the unoccupied glucocorticoid re- ceptor localizing to the nucleus. Once the glucocorticoid binds to the glucocorticoid receptor, Hsp90 dissociates, allowing the rapid nuclear localization of the acti- vated glucocorticoid receptor-